WO2001019790A1 - Derives de prostaglandine - Google Patents

Derives de prostaglandine Download PDF

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Publication number
WO2001019790A1
WO2001019790A1 PCT/JP2000/006162 JP0006162W WO0119790A1 WO 2001019790 A1 WO2001019790 A1 WO 2001019790A1 JP 0006162 W JP0006162 W JP 0006162W WO 0119790 A1 WO0119790 A1 WO 0119790A1
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WO
WIPO (PCT)
Prior art keywords
group
cyclohexyl
hydrogen
formula
methyl
Prior art date
Application number
PCT/JP2000/006162
Other languages
English (en)
Japanese (ja)
Inventor
Fumie Sato
Tohru Tanami
Hideo Tanaka
Naoya Ono
Makoto Yagi
Hitomi Hirano
Original Assignee
Taisho Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to DE60043702T priority Critical patent/DE60043702D1/de
Priority to EP00957064A priority patent/EP1211242B1/fr
Priority to US10/070,643 priority patent/US6740772B1/en
Priority to CA002384718A priority patent/CA2384718C/fr
Priority to JP2001523370A priority patent/JP4563636B2/ja
Priority to DK00957064.9T priority patent/DK1211242T3/da
Priority to AU68767/00A priority patent/AU766983B2/en
Priority to AT00957064T priority patent/ATE455098T1/de
Publication of WO2001019790A1 publication Critical patent/WO2001019790A1/fr
Priority to HK03100663.3A priority patent/HK1048466B/zh

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups

Definitions

  • the present invention relates to a novel prostaglandin derivative, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • P GD 2 has the already known to be a humoral factor that regulates the expression and maintenance of sleep that put in the brain, sleep induced by P GD 2 in monkeys, spontaneous on EEG and behavioral It has become clear that it is indistinguishable from natural sleep (Pro Natl. Acad. Sci. USA, Vol. 85, pp. 4082-4086 (1988)), and is expected as a compound having a new sleep-inducing effect. .
  • PGD derivatives including PGD 2 have not been put into practical use due to problems such as the ability to enter the brain and stability. Further, the PG derivatives other than P GD 2 derivatives, there is no report with concrete description about sleep-inducing action.
  • An object of the present invention is to provide a novel p G derivatives having Agonisuto activity and sleep-inducing effects of P GD 2 like. Disclosure of the invention
  • X represents an ⁇ - or tri-substituted halogen atom
  • ⁇ represents an ethylene group, a vinylene group or an ethynylene group
  • n represents an integer of 15, p represents 0 or 2, q represents an integer of 13, and r represents 0 or 1.
  • R 1 is C 3 -t. Cycloalkyl group, C 4 alkyl C 3- . Cycloalkyl group, C 3 - 10 cycloalkyl C alkyl group, Cs-i. Alkyl group, C 5 - i. Alkenyl group,
  • C 5 - Represents an alkynyl group or a bridged cyclic hydrocarbon group
  • R 2 is a hydrogen atom, C! .
  • n 0 1 or 2.
  • the present invention is also a medicament comprising a compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
  • the vinylene group is a cis or trans vinylene group.
  • Haloge A fluorine atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • ⁇ 3 - 1 means a cycloalkyl group of 3-1 0 carbon atoms and the cycloalkyl group include such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc. heptyl group cyclohexylene .
  • the cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms substituted by a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methylcyclopropyl group, methylcyclohexyl And an ethylcyclohexyl group.
  • a cycloalkyl C t- 4 alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a cycloalkyl group having 3 to 10 carbon atoms, for example, cyclopropylmethyl Group, cyclobutylmethyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethyl group, cycloheptylmethyl group and the like.
  • the alkyl group means a linear or branched alkyl group having 5 to 10 carbon atoms, such as benzyl, hexyl, heptyl, octyl, 1-methylpentyl, and 2-methylpentyl.
  • the alkenyl group means a linear or branched alkenyl group having 5 to 10 carbon atoms, such as 3-pentenyl, 4-hexynyl, 5-heptenyl, 4-methyl-3 —Pentenyl, 2,4-dimethylpentenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl and the like.
  • the alkynyl group means a linear or branched alkynyl group having 5 to 10 carbon atoms, for example, 3-pentynyl, 3-hexynyl, 4-hexynyl, 1-methylpenta-3 —Ynyl group, 2-methylpenter-3-ynyl group, 1-methylhexyl 3-ynyl group, 2-methylhexyl 3-ynyl group and the like.
  • Examples of the crosslinked cyclic hydrocarbon group include a bornyl group, a norbornyl group, an adamantyl group, a pinanyl group, a phenyl group, a caryl group, and a camphanyl group. You.
  • the alkyl group means a linear or branched alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a tert-butyl group. And a pentyl group, an isopentyl group, a 2-ethylpropyl group, a hexyl group, an isohexyl group, a 1-ethylbutyl group, a heptyl group, an isoheptyl group, an octyl group, a nonyl group, and a decyl group.
  • Pharmaceutically acceptable salts include, for example, salts with alkaline metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine And salts with pyridine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, tetraalkylammonium, and tris (hydroxymethyl) aminomethane.
  • alkaline metals such as sodium and potassium
  • alkaline earth metals such as calcium and magnesium
  • ammonia methylamine, dimethylamine, cyclopentylamine
  • Preferred compounds of the present invention are those of the formula (I) wherein R 1 is Ca 2. Cycloalkyl group,
  • Cycloalkyl group, C A cycloalkyl C alkyl group,. A branched alkyl group,. A branched alkenyl group,.
  • the compound is a branched alkynyl group or a bridged cyclic hydrocarbon group. More preferably, in the formula (I), X is an ⁇ - or / 3-substituted chlorine atom or bromine atom, and R 1 is Cycloalkyl group, Ci. Cycloalkyl C alkyl group or C 2. A branched alkenyl group, wherein R 2 is a hydrogen atom or C,. A compound that is an alkyl group.
  • Y is preferably a vinylene group or an ethynylene group, and more preferably an ethynylene group.
  • A is the formula S (0) P (CH 2 ) n , the formula S (0) P (CH 2 ) q S (0) P (CH 2 ) r or the formula S (0) P (CH 2 ) q O (CH 2 ) a group represented by r is preferable, and further a formula S (CH 2 ) n
  • a group represented by S (CH 2 ) r or a formula S (CH 2 ) Q ⁇ (CH 2 ) r is more preferable.
  • Compounds of formula (I) can be prepared, for example, by the methods summarized in the following reaction schemes.
  • a 1 is the formula 0 (CH 2 ) n , the formula S (CH 2 ) n , the formula 0 (CH 2 ) q O (CH 2 ) r , the formula 0 (CH 2 ) q S (CH 2 ) r , Formula S (CH 2 ) l S ( ⁇ 11 2 ) "or Formula 3 (CH 2 ). 0 (CH 2 ) r
  • Y ′ represents an ethylene group or a vinylene group
  • R 3 represents a C alkyl group or C.
  • TBS represents a tert-butyldimethylsilyl group
  • X, Y, R 1 and m are as defined above.
  • a compound in which Y is an ethylene group or a vinylene group that is, a compound in which Y is Y ′
  • a compound of the formula ( ⁇ ) is used at 178 to 0 ° C.
  • a compound in which Y is an ethynylene group is obtained.
  • the compound of the formula (0) is reacted at 0 to 30 ° C.
  • bases for example, organic resins such as triethylamine, diisopropylamine, pyridine, and dimethylaniline
  • base resins such as polyvinylpolypyrrolidone, diisopropylaminomethyl-polystyrene, and (piperidinomethyl) polystyrene are used.
  • a divalent palladium complex or complex salt eg, dichlorobis (acetonitrile) palladium ( ⁇ ), dichlorobis (benzonitrile) palladium ( ⁇ ), palladium chloride, etc.
  • the reaction can also be carried out in an inert solvent (for example, benzene, toluene, xylene, n-hexane, n-pentane, acetone, etc.) using —1 to The compound of VII) can be obtained.
  • bromination and fluorination can also be performed by a usual method.
  • bromination can be obtained by reacting 1 to 10 equivalents of carbon tetrabromide in acetonitrile in the presence of 1 to 10 equivalents of triphenylphosphine and 1 to 10 equivalents of pyridine.
  • Fluorination can be obtained, for example, by reacting 5 to 20 equivalents of getylaminosulfur trifluoride (DAST) in methylene chloride.
  • DAST getylaminosulfur trifluoride
  • the compound of formula (K) (or formula (IX ')) is treated with methanol, ethanol, acetonitrile, or a mixed solvent thereof using hydrofluoric acid, pyridinium poly (hydrogen fluoride), hydrochloric acid, or the like.
  • the ten-butyldimethylsilyl group is removed under a condition usually used in a mixed solvent of water and water to obtain a PG derivative of the formula (Ia) (or (Ia ')) of the present invention.
  • the compound of formula (Ia) is mixed with a buffer such as a phosphate buffer or a tris-hydrochloride buffer using an organic solvent (a water, such as acetone, methanol or ethanol), if necessary.
  • a buffer such as a phosphate buffer or a tris-hydrochloride buffer using an organic solvent (a water, such as acetone, methanol or ethanol), if necessary.
  • the PG derivative (Ib) of the present invention is obtained by hydrolysis by reacting with an enzyme.
  • enzymes include enzymes produced by microorganisms (for example, enzymes produced by microorganisms belonging to the genus Candida and Pseudomonas) and enzymes produced from animal organs (for example, enzymes prepared from pig liver and pig liver).
  • lipase VII manufactured by Sigma and derived from Candida spp.
  • Lipase AY manufactured by Amano Pharmaceutical and derived from Candida spp.
  • And lipase PS examples include lipase VII (manufactured by Sigma and derived from Candida spp.), Lipase AY (manufactured by Amano Pharmaceutical and derived from Candida spp.), And lipase PS.
  • the amount of the enzyme to be used may be appropriately selected depending on the enzyme titer and the amount of the substrate [compound of the formula (la)], but is usually 0.1 to 20 times the weight of the substrate.
  • the reaction temperature is 25-50 ° C, preferably 30-40 ° C.
  • the PG derivative of the formula (Id) (or the formula (Id ')) of the present invention is obtained by hydrolyzing the compound of the formula Uc) (or the formula Uc')) in the same manner as in the above (6). Is obtained.
  • the oxidation of the formula (Id) (or the formula (Id ')) of the present invention can also be carried out by oxidizing it using the formula (lb) (or the formula (lb')) in the same manner as in the above (7).
  • a PG derivative can be obtained.
  • typical compounds of the present invention the following can be mentioned.
  • Chill hydrogen aa ⁇ -C1 c o c 2 SCH2 To cyclo. To methylcycloalkyl aa ⁇ -C1 c 0 S (CH 2 ) 3 cyclo. To methyl cyclohexyl aa ⁇ -C1c2c2SCH2 cyclo.
  • (E) CH CH: trans-vinylene
  • (Z) CH CH: cis-vinylene
  • 8-position bonding between the 7-position carbon atom and 8-position carbon atom
  • 15-position bonding between the 15-position carbon atom and the hydroxyl group
  • preparation for oral administration for example, tablets, powders, granules, powders, capsules, solutions, emulsions, suspensions and the like can be used, and these can be produced by a usual method.
  • aqueous or non-aqueous solutions, emulsions, suspensions, solid preparations to be used by dissolving in an injection solvent immediately before use, and the like can be used.
  • the compound of the present invention can be formulated by forming an inclusion compound with, for example, 3 or 1-cyclodextrin or methylated cyclodextrin.
  • the aqueous or non-aqueous solution, emulsion, suspension and the like can be administered by injection or the like.
  • the dosage varies depending on the age, body weight, etc., but it is 1 ng to 1 mgZ for adults, and the dose is administered once or several times a day.
  • Triethyl borane (1.0 M) was added to a toluene (32 m 1) solution of the compound (3.86 g) obtained in the above (1) and methyl ester of 5-mercaptopentanoate (1.64 g).
  • a hexane solution, 0.8 lm 1) were added at 0 ° C under an argon atmosphere, and the mixture was left overnight at the same temperature.
  • the reaction mixture was purified by silica gel column chromatography to obtain 6-thia-16,17,18,19,20-pentanol-15-cyclohexyl-13,14-didehydro-PGE! Methyl ester 11,15-bis (tert-butyldimethylsilyl ether) (1.02 g) was obtained.
  • Lithium hydroxide monohydrate (67 mg) was added to a solution of the compound obtained in Example 1 (133 mg) in methyl alcohol (10.6 ml)-7K (1.06 ml), and the mixture was stirred at room temperature overnight. did.
  • the mixture was made weakly acidic with 1 M hydrochloric acid, extracted with ethyl acetate, and the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain the title compound (12 Omg).
  • Example 1 The compound obtained in (1) (1.60 g) and 4-oxa-6-hexahexane Tributyltin hydride (2.25 ml) and triethylborane (1.0 M, hexane solution, 0.34 ml) in a toluene (13.5 ml) solution of acid methyl ester (2.16 g) in an argon atmosphere Then, the mixture was added at 0 ° C and left overnight at the same temperature.
  • reaction mixture was purified by silica gel column chromatography to give 4-oxa-16,17,18,19,20-pentanol-15-cyclohexyl-13,14-didehydro-PGE methyl ester 11,15- Bis (tert-butyldimethylsilyl ether) (1.22 g) was obtained.
  • Example 3 (1) was substantially the same as Example 3 (1) except that 4-thia-6-iodohexanoic acid methyl ester was used instead of 4-oxa-6-iodohexanoic acid methyl ester. Similarly, 4-thia-16,17,18,19,20-pentanor-15-cyclohexyl-13,14-didehydro-PGE! The ethyl ester 11,15-bis (tert-butyldimethylsilyl ether) was obtained.
  • Example 5 Using the compound obtained in Example 5, the title compound was obtained in substantially the same manner as in Example 4.
  • Example 7 (1) (3R) -1- instead of (IE, 3S) -1-odo-3- (tert-butyldimethylsiloxane) -3-cyclohexyl-1-propene
  • Example 3 (3R, 4R) -2-methylene-3-[[(-)-3- (tert-butyldimethylsiloxy) -3-cyclohexylpropane was obtained in substantially the same manner as in Example 7 (1).
  • 3R) -3- (Lert-butyldimethylsiloxy) -3-cyclohexyl-1-propyl] -4- (tert-butyldimethylsiloxy) cyclopenten-1-one was obtained.
  • Example 1 (2) 5-mercapto-3-thiapentanoic acid methyl ester was used in place of 5-mercaptopentanoic acid methyl ester, and substantially the same as in Example 1 (2). , 6-Dithia-16,17,18,19,20-pentyl nor-15-cyclohexyl-13,14-didehydro-PGE methyl ester 11,15-bis (tert-butyldimethylsilyl ether) was.
  • Example 13 Using the compound obtained in Example 13 and in substantially the same manner as in Example 2, the title compound was obtained.
  • the drug concentration required to produce a PGD 2 1 0 a c AMP weight determined by adding a concentration of M 1 0 0% and the a-outs 50% of c AMP amounts, EC 5. It was obtained as a value.
  • the present invention compounds exhibit Agonisuto action of prostaglandin D 2 like, renal diseases, ischemic heart disease and heart failure are useful as cardiovascular diseases and a therapeutic agent, such as glaucoma, such as hypertension.
  • the compound of the present invention has a sufficient sleep-inducing effect, and is also excellent in stability and translocation into the brain, and is useful as a drug having a sleep-inducing effect.

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Abstract

L'invention concerne des dérivés de prostaglandine représentés par la formule générale (I), des sels de ceux-ci pharmaceutiquement acceptables, ou des hydrates des deux. Dans cette formule, X représente un halogéno α ou β substituant; Y représente éthylène, vinylène, ou éthynylène; A représente O(CH2)n, S(O)p(CH2)n, O(CH2)qO(CH2)r, O(CH2)qS(O)p(CH2)r, S(O)p(CH2)qS(O)p(CH2)r, (où n est un nombre entier compris entre 1 et 5; p est égal à 0, 1, ou 2; q est un nombre entier compris entre 1 et 3; et r est égal à 0 ou 1); R1 représente cycloalkyle C3-10, alkyle C1-4, alcényle C5-10, alcynyle C5-10, ou un groupe hydrocarboné cyclique ponté; R2 représente H, alkyle C1-10, ou cycloalkyle C3-10; et m est égal à 0, 1, ou 2. Ces composés sont nouveaux et possèdent une activité agoniste de la prostaglandine de type D2, et un effet induisant le sommeil.
PCT/JP2000/006162 1999-09-10 2000-09-08 Derives de prostaglandine WO2001019790A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
DE60043702T DE60043702D1 (de) 1999-09-10 2000-09-08 Prostaglandin-derivate
EP00957064A EP1211242B1 (fr) 1999-09-10 2000-09-08 Derives de prostaglandine
US10/070,643 US6740772B1 (en) 1999-09-10 2000-09-08 Prostaglandin derivatives
CA002384718A CA2384718C (fr) 1999-09-10 2000-09-08 Derives de prostaglandine
JP2001523370A JP4563636B2 (ja) 1999-09-10 2000-09-08 プロスタグランジン誘導体
DK00957064.9T DK1211242T3 (da) 1999-09-10 2000-09-08 Prostaglandinderivater
AU68767/00A AU766983B2 (en) 1999-09-10 2000-09-08 Prostaglandin derivatives
AT00957064T ATE455098T1 (de) 1999-09-10 2000-09-08 Prostaglandin-derivate
HK03100663.3A HK1048466B (zh) 1999-09-10 2003-01-24 前列腺素衍生物

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP11/256727 1999-09-10
JP25672799 1999-09-10
JP32380499 1999-11-15
JP11/323804 1999-11-15
JP2000189121 2000-06-23
JP2000/189121 2000-06-23

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WO2001019790A1 true WO2001019790A1 (fr) 2001-03-22

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US (1) US6740772B1 (fr)
EP (1) EP1211242B1 (fr)
JP (1) JP4563636B2 (fr)
KR (1) KR100698433B1 (fr)
CN (1) CN1222509C (fr)
AT (1) ATE455098T1 (fr)
AU (1) AU766983B2 (fr)
CA (1) CA2384718C (fr)
DE (1) DE60043702D1 (fr)
DK (1) DK1211242T3 (fr)
ES (1) ES2337981T3 (fr)
HK (1) HK1048466B (fr)
PT (1) PT1211242E (fr)
WO (1) WO2001019790A1 (fr)

Cited By (4)

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JP2005247842A (ja) * 2004-02-06 2005-09-15 Taisho Pharmaceut Co Ltd 乾皮症治療剤
US7718701B2 (en) * 2002-08-09 2010-05-18 Taisho Pharmaceutical Co., Ltd. Antipruritic agent
US7737182B2 (en) * 2002-08-09 2010-06-15 Taisho Pharmaceutical Co., Ltd. Pharmaceuticals for xerosis
US7763652B2 (en) * 2002-07-12 2010-07-27 Taisho Pharmaceutical Co., Ltd. Prostaglandin derivatives

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US20040266880A1 (en) * 2002-02-22 2004-12-30 Fumie Sato Antipruritics
AU2003301900A1 (en) * 2002-11-13 2004-06-03 Fumie Sato Antipruritic drug

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IL87116A (en) 1987-07-17 1993-03-15 Schering Ag 9-halogen-(z)-prostaglandin derivatives and pharmaceutical compositions containing the same
US5891910A (en) 1987-07-17 1999-04-06 Schering Aktiengesellschaft 9-halogen-(Z) prostaglandin derivatives, process for their production and their use as pharmaceutical agents
JP2502009B2 (ja) 1992-06-08 1996-05-29 サンデン株式会社 自動販売機
JP3502952B2 (ja) * 1992-10-20 2004-03-02 大正製薬株式会社 プロスタグランジン誘導体
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Publication number Priority date Publication date Assignee Title
WO1992008697A2 (fr) * 1990-11-09 1992-05-29 Schering Aktiengesellschaft, Berlin Und Bergkamen DERIVES DE LA 9-HALOGENE-11β-HYDROXYPROSTAGLANDINE, PROCEDES DE FABRICATION ET APPLICATION COMME MEDICAMENT
WO1994008959A1 (fr) * 1992-10-20 1994-04-28 Taisho Pharmaceutical Co., Ltd. Derive de prostaglandine
WO1995006634A1 (fr) * 1993-08-31 1995-03-09 Schering Aktiengesellschaft Nouveaux derives de 9-chloroprostaglandine
WO1995018101A1 (fr) * 1993-12-29 1995-07-06 Taisho Pharmaceutical Co., Ltd. Derive de prostaglandine, son sel et utilisation de ce compose
JPH07285929A (ja) * 1994-04-19 1995-10-31 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7763652B2 (en) * 2002-07-12 2010-07-27 Taisho Pharmaceutical Co., Ltd. Prostaglandin derivatives
US7718701B2 (en) * 2002-08-09 2010-05-18 Taisho Pharmaceutical Co., Ltd. Antipruritic agent
US7737182B2 (en) * 2002-08-09 2010-06-15 Taisho Pharmaceutical Co., Ltd. Pharmaceuticals for xerosis
JP2005247842A (ja) * 2004-02-06 2005-09-15 Taisho Pharmaceut Co Ltd 乾皮症治療剤

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CA2384718A1 (fr) 2001-03-22
ATE455098T1 (de) 2010-01-15
KR20020043581A (ko) 2002-06-10
CN1373752A (zh) 2002-10-09
DK1211242T3 (da) 2010-04-26
AU766983B2 (en) 2003-10-30
AU6876700A (en) 2001-04-17
HK1048466B (zh) 2006-04-07
JP4563636B2 (ja) 2010-10-13
EP1211242A4 (fr) 2004-11-03
EP1211242A1 (fr) 2002-06-05
ES2337981T3 (es) 2010-05-03
KR100698433B1 (ko) 2007-03-22
CA2384718C (fr) 2009-12-01
CN1222509C (zh) 2005-10-12
US6740772B1 (en) 2004-05-25
DE60043702D1 (de) 2010-03-04
EP1211242B1 (fr) 2010-01-13
HK1048466A1 (en) 2003-04-04
PT1211242E (pt) 2010-02-10

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